title: Sizes of interface residues account for cross-class binding affinity patterns in Eph receptor-ephrin families.
abstract: Eph receptors comprise the largest known family of receptor tyrosine kinases in mammals. They bind members of a second family, the ephrins. As both Eph receptors and ephrins are membrane bound, interactions permit unusual bidirectional cell-cell signaling. Eph receptors and ephrins each form two classes, A and B, based on sequences, structures, and patterns of affinity: Class A Eph receptors bind class A ephrins, and class B Eph receptors bind class B ephrins. The only known exceptions are the receptor EphA4, which can bind ephrinB2 and ephrinB3 in addition to the ephrin-As (Bowden et al., Structure 2009;17:1386-1397); and EphB2, which can bind ephrin-A5 in addition to the ephrin-Bs (Himanen et al., Nat Neurosci 2004;7:501-509). A crystal structure is available of the interacting domains of the EphA4-ephrin B2 complex (wwPDB entry 2WO2) (Bowden et al., Structure 2009;17:1386-1397). In this complex, the ligand-binding domain of EphA4 adopts an EphB-like conformation. To understand why other cross-class EphA receptor-ephrinB complexes do not form, we modeled hypothetical complexes between (1) EphA4-ephrinB1, (2) EphA4-ephrinB3, and (3) EphA2-ephrinB2. We identify particular residues in the interface region, the size variations of which cause steric clashes that prevent formation of the unobserved complexes. The sizes of the sidechains of residues at these positions correlate with the pattern of binding affinity.
authors.affiliation: Department of Biochemistry and Molecular Biology and The Huck Institute of Genomics, Proteomics and Bioinformatics, The Pennsylvania State University, University Park, Pennsylvania, 16802.
authors.forename: Fei-Yi
authors.initials: FY
authors.lastname: Guo
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Lesk
mesh_terms: D000595:Amino Acid Sequence; D036342:Ephrins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D036122:Receptor, EphA4 / Q000737:chemistry* / Q000378:metabolism*; D016415:Sequence Alignment; D013499:Surface Properties
chemical_list: D036342:Ephrins; D036122:Receptor, EphA4
keywords: Eph receptor-Ephrin binding; cross-class affinity patterns; developmental control; interface residues; receptor tyrosine kinase